Ghrelin is a peptide hormone discovered in 1999 that is known to promote the secretion of growth hormone (GH). Ghrelin promotes GH secretion via receptors different from those for growth hormone-releasing hormone (GHRH). The peptide chain of ghrelin comprises 28 amino acid residues, in which the hydroxyl group of the third serine is acylated with octanoic acid (active ghrelin); but non-acylated ghrelin (desacyl ghrelin) does not exhibit GH secretion activity.
Various physiological active mechanisms of ghrelin are known; and for example, ghrelin is known to increase appetite, protect the cardiovascular system, and control metabolism among other effects, in addition to the above-mentioned GH secretion-promoting effect. These known effects of ghrelin suggest that the possibility of its application to therapeutic agents for diseases such as cibophobia, myocardial infarction, heart failure, and cachexia as well as those to prevent aging/dwarfism (Non-Patent Document 1). Moreover, it is reported that ghrelin promotes neurite extension and improves nerve paralysis (including movement disorders and perceptual disorders) associated with peripheral nerve diseases such as amyotrophic lateral sclerosis, diabetic neurological disorder, neuropathy, neurological disorder caused by traumatic neural damage or neural deficiency, toxic neurological disorder and multiple sclerosis. It also improves memory disorders in patients with central nerve disorders and diseases such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease and spinal injury; it is useful in the treatment of dementia and for brain function activation; as well as to treat and prevent amyotrophic lateral sclerosis and diabetic neurological disorder (Patent Document 1). It is also known for its activation of osteoblasts and bone reconstitution in dwarfism and normal persons; increase of muscle mass and muscle strength in GH-deficient adults; improvement of exercise capacity in GH-deficient adults; and cure of severe burns in children. It is used in combination with gonadotropin to induce ovulation; in the prevention of protein metabolism disorder due to prednisone administration; in the promotion of T-cell education in severe immunodeficiency; and prevention of senile weight loss, fatty tissue extension and skin atrophy. As for the effects of ghrelin in patients with disorders not directly related to GH deficiency or depression, ghrelin may, for example, increase heart beating and is therefore known to be effective in cardiac diseases such as heart failure (Patent Document 2). Also known are its effects on myocardial infarction, reperfusion injury in bypass surgery or PTCA for myocardial infarction, coronary microcirculation failure, myocarditis (alcoholic, viral, etc.), dilated cardiomyopathy, cardiac transplantation, arrhythmia, heart failure, and also drug-induced myocardial disorders caused by chemotherapeutical agents or the like (Patent Document 3). In addition, it has been confirmed that ghrelin administration to patients with chronic obstructive pulmonary disease (COPD) results in an increase of respiration muscle power, body weight and skeletal muscle mass, as well as in an improvement of the QOL score and the 6-minute walking distance; it is also reported that ghrelin may be expected to improve various symptoms of COPD (Non-Patent Document 2).
As in the above, various excellent physiological effects of ghrelin have been specifically noted, and the development of pharmaceuticals comprising ghrelin as the active ingredient has been promoted. However, few substances have heretofore been known capable of promoting ghrelin production in living bodies.
Patent Document 1: JP-A 2005-239712
Patent Document 2: Re-issued WO03097083
Patent Document 3: Re-issued WO04014412
Non-Patent Document 1: Proceedings the 124th Symposium of the Japanese Association of Medical Science, pp. 45-52
Non-Patent Document 2: New Current 16 (27), pp. 17-22